During aging, skeletal muscles become atrophic and lose contractile force. This affects a large population of elderly regardless of ethnicity, gender, and wealth and is the most common cause of age-related loss of independence, frailty, and mortality. As the elderly proportion in the population continues to increase, the potential social and economic burden of muscle aging is becoming enormous. The neuromuscular junction is a synapse between motor neuron terminals and skeletal muscle fibers that transmit signals from motor neurons to muscle fibers. The neuromuscular transmission is critical for the control of muscle contraction and is thus essential for our physical mobility and daily life. Extensive research has revealed insight into the pathophysiological mechanisms of muscle aging. However, although NMJ structures and functions are disrupted in aged animals, little is known about underlying mechanisms. In contrast to NMJ formation, which has been studied extensively, much less is understood about mechanisms of NMJ maintenance, in particular in aged animals. This proposal will test an innovative hypothesis that NMJ function in aged animals depends on agrin signaling, a pathway that is required for NMJ formation. In particular, we will address the following critical questions by using a combination of cutting edge technologies. First, does LRP4 deficiency mimicking LRP4 reduction in aged mice cause NMJ decline? Does restoring agrin signaling improve NMJ function in aged mice? What is the mechanism that controls LRP4 stability? How does agrin signaling maintain NMJ function in aged mice? Results will provide unequivocal evidence to either support or refute that agrin signaling is involved in NMJ decline during aging, reveal whether enhancing agrin signaling may prevent or delay NMJ decline and muscle aging, and identify novel mechanisms controlling LRP4 stability and mediating agrin signaling to promote NMJ maintenance. Such knowledge may contribute to a better understanding of molecular mechanisms of NMJ decline and muscle aging, which is prerequisite to the development of effective therapeutic interventions for NMJ decline and muscle aging.